Generally, the invention relates to pharmaceutical compositions of drugs and concentration-enhancing polymers which increase the drug concentration in a use environment and thus increase bioavailability.
Low-solubility drugs often show poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, fed state of the patient, and form of the drug. Increasing the bioavailability of low-solubility drugs has been the subject of much research. Increasing bioavailability hinges on improving the concentration of the drug in solution to improve absorption.
It is known that many low-solubility drugs can be formulated so as to increase the maximum concentration of the drug that will dissolve in an aqueous solution in in vitro tests. One such approach is to grind the drug down to less than 400 nm to form so-called nanoparticles. The nanoparticles contain a discrete phase of a drug with a surface modifier adsorbed to the surface. When such a drug in a nanoparticle form is initially administered to an environment of use, such as in gastric fluid, the nanoparticle form of the drug may lead to increased bioavailability. See U.S. Pat. No. 5,145,684, herein incorporated by reference.
Another drug delivery technology used to increase concentration of a drug in a use environment is to incorporate the drug into particles of a water-swellable but insoluble crosslinked polymer, contacting this composition with a solvent, in gaseous or liquid form, which is able to swell the polymer, and then drying the product under vacuum. See U.S. Pat. No. 5,569,469, incorporated herein by reference in its entirety.
Yet another drug delivery technology converts the bulk crystalline drug into an amorphous nanoparticle. Essentially, a suspension of drug in solvent is fed into a chamber, where it is rapidly mixed with another solvent. The drug substance suspension is converted into a molecular solution. The admixture of an aqueous solution of a polymer induces precipitation of the drug. The polymer keeps the drug substance particles in their nanoparticulate state and prevents them from aggregation or growth. Water redispersable dry powders can be obtained from the nanosized dispersion by conventional methods. See U.S. Pat. No. 6,197,349 also incorporated by reference.
Another drug delivery technology of increasing dissolution rate of drug in a use environment is through incorporating the drug in a nanosuspension. See U.S. Pat. No. 5,858,410, herein incorporated by reference. A nanosuspension is a suspension of nanosized (typically 10 nm to 1000 nm) particles of at least one active therapeutic.
U.S. Pat. No. 6,177,103, herein incorporated by reference, discloses a process for preparing stabilized suspensions of water insoluble drugs with an average particle size of 50 nm to about 2000 nm. The suspensions are prepared by rapid expansion of a solution of the drug, surface modifier and a liquefied gas (e.g., a supercritical fluid) into an aqueous medium. The aqueous suspension may also be homogenized using a high-pressure homogenizer. See also U.S. Pat. No. 5,858,410 also incorporated by reference.
U.S. Pat. No. 5,560,932, herein incorporated by reference, discloses a process for preparing extremely small particles with average particle diameters of less than 400 nm by homogeneous nucleation and precipitation in the presence of a surface modifier.
Stabilizing the amorphous form of a drug by spray-drying the drug in the presence of a stabilizer to inhibit crystal growth is also known to increase solubility of low solubility drugs. See U.S. Pat. Nos. 4,769,236 and 4,610,875, both of which are herein incorporated by reference.
U.S. Pat. Nos. 5,851,275 and 5,686,133, herein incorporated by reference, disclose another drug delivery technology for increasing the dissolution rate of poorly soluble drugs by coating them with a combination of gelatin and lecithin.
In all of the above cases, the methods often provide an increase in dissolution rate and/or a temporary increase in the solubility of the drug in a use environment.
Increasing drug solubilization by using combinations of drug and polymer has been described. For example, Martin et al., U.S. Pat. No. 4,344,934 mixed poorly soluble drugs with polymers such as hydroxypropyl methyl cellulose (HPMC) and added an aqueous surfactant solution to the drug-polymer mixture. While this results in improved dissolution, there is only slight enhancement of drug concentration relative to the equilibrium concentration. Piergiorgio et al., U.S. Pat. No. 4,880,623 used solvent processing to co-precipitate nifedipine with PEG and adsorbed this onto polymers such as HPMC, or onto other excipients. While increased drug bioavailability in a controlled release dosage form, relative to the commercial product nifedipine. ADALAT AR, was observed, no direct comparison was made between coprecipitated and noncoprecipitated drug forms. Uedo et al., U.S. Pat. No. 5,093,372 mixed the sparingly-soluble drug exifone with polymers such as HPMC to increase bioavailability. However, the results were reported to be unique for exifone formulations, and the exifone was not in a solubility-improved form.
Usui, et al., Inhibitory Effects of Water-soluble Polymers on Precipitation of RS-8359, Int'l J. of Pharmaceutics 154 (1997) 59-66, discloses the use of three polymers, namely hydroxy propyl methyl cellulose, hydroxy propyl cellulose, and polyvinylpyrrolidone to inhibit precipitation of the low-solubility drug RS-8359. The drug and polymer were dissolved in a mixture of 0.5 N HCl and methanol, and then added to a phosphate buffer solution. Usui et al. observed that the particular polymers inhibited crystallization of the drug.
Nevertheless, what is still needed is a composition comprising a low-solubility drug that provides enhanced concentration of the drug in aqueous solution and/or that enhances the bioavailability of the drug. These needs and others that will become apparent to one of ordinary skill in the art are met by the present invention, which is summarized and described in detail below.